Individual differences in initial sensitivity to nicotine may play a significant role in determining whether or not a person becomes a smoker. In people with high susceptibility, the initial response to nicotine seems to include not only aversive effects but also reinforcing consequences such as pleasurable effects and temporary improvements in affect or performance, and further exposure leads to rapid development of tolerance to aversive effects and sensitization of positive effects, resulting in nicotine dependence. The concentration of people with high susceptibility among those who continue to smoke may explain the difficulty encountered in reducing the prevalence of smoking much below 25 percent over the past decade. To manage this important public health problem more effectively, there is a pressing need to identify the individual behavioral and biological characteristics that set the stage for nicotine reinforcement as well as those factors that interfere with it. The proposed research involves comparisons of sensitivity to nicotine in people who have a positive or a negative family smoking history; never smokers have been chosen for study, rather than current or former smokers, in order to avoid the influence of extensive nicotine exposure on tolerance and sensitization. The approach is comparable to that which has been employed to study the children of alcoholics and other drug abusers. Over a five-year period, the responses of men and women with positive or negative family histories will be investigated, employing both within-subject and between group comparisons. The reinforcement potential of nicotine will be explored by determining reactivity to nicotine administration via nasal spray; subjective, physiological, cognitive, and neuroendocrine response systems will be examined to provide a multi-dimensional assessment. Determination of differences in initial reactivity to nicotine along with identification of baseline characteristics that may contribute to nicotine reinforcement, such as personality variables, psychiatric cofactors, and environmental factors, should increase the understanding of the conditions that promote or protect against smoking behavior, providing the basis for more effective prevention programs and more efficient treatment interventions.